The release of retrovirus particles from the infected cell is greatly stimulated by late domains present within the Gag precursor protein. We played a key early role in this field by identifying the PTAP late domain of HIV-1, and subsequent studies from our lab and others demonstrated that late domains function by interacting with components of the endosomal sorting (ESCRT) machinery. We continue to be actively involved in elucidating the host cell machinery involved in the release of HIV-1 and other lentiviruses (e.g., EIAV and FIV) and have initiated a high-throughput screen with the NIH Chemical Genomics Center to identify small-molecule inhibitors of HIV-1 budding. We have also initiated studies aimed at defining the mechanism by which the recently discovered host restriction factor CD317 (tetherin) blocks HIV-1 release and the process by which the viral protein Vpu counteracts this restriction. [Corresponds to Freed Project 2 in the April 2007 site visit report of the HIV Drug Resistance Program]